scholarly journals Central Memory T-Cell Differentiation Correlates with Depth of Response in Relapsed/Refractory Multiple Myeloma Patients Receiving Elotuzumab in Combination with Carfilzomib, Lenalidomide and Dexamethasone (Elo-KRd)

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1585-1585
Author(s):  
David M Foureau ◽  
Manisha Bhutani ◽  
Fei Guo ◽  
Kateryna Fesenkova ◽  
Shebli Atrash ◽  
...  
Keyword(s):  
T Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
Nk Cell ◽  
Central Memory ◽  
Cell Maturation ◽  
Cytotoxic T Cell ◽  
Advisory Committees ◽  
Post Induction ◽  
Cell Conversion

Abstract Introduction: The addition of elotuzumab (Elo), an anti SLAMF7 immunostimulatory antibody, to carfilzomib, lenalidomide and dexamethasone (KRd) can lead to synergistic anti-myeloma immune effects. Pre-clinical data showed that both Elo and KRd promote innate NK cell response and adaptive cytotoxic T cell response. Here we report longitudinal NK and T cell profiling data in relation to clinical response and MRD status in the context of an Elo-KRd Phase II study (NCT03361306). Methods: Patients with relapsed refractory multiple myeloma (RRMM) after first-line therapy who enrolled in this phase II study received treatment with 4 cycles of Elo-KRd induction followed by Elo-Rd maintenance. Peripheral blood (PB) specimens were collected pre-induction (n=15), after induction (n=14), and every other month during maintenance (n=10). Bone marrow (BM) aspirates were collected pre- and post-induction and at the time of CR confirmation. Minimal residual disease (MRD) was assessed by next-generation flow cytometry (MRD NGF, 10 -5 sensitivity) post-induction for patients achieving very good partial response or better (≥VGPR). PB and BM NK, CD4 and CD8 T cell subset distribution, activation and anergy status were assessed by flow cytometry. Longitudinal Elo-KRd immune modulatory effect was modelled by polynomial regression analyses. Wilcoxon signed rank tests were used for timepoints comparisons. Mann-Whitney U tests were used for response groups comparisons between. Population frequency data, among mononuclear cells, are presented as mean±SD unless otherwise noted. Results: We first investigated Elo-KRd immune modulatory activity during induction treatment. Immature / mature NK cell distribution in PB remained unaltered pre- and post-induction (iNK: 8.9±6.4 vs 8.6±3.5, p=0.808; mNK: 14.9±6.8 vs 13.1±6.1, p=0.463). No significant change in PB NK activation markers KIR2DS4, KIR3DL1, NKG2A, NKG2D or NKp46 was observed throughout Elo-KRd induction. A lack of NK cell maturation was also observed in the BM despite a rise of iNK NKG2D expression (iNK NKG2D+: 22.5±7.7 vs 30.1±8.8, p=0.0.039). The number of both PB effector T helper (CD4+ Th) and cytotoxic T cell (CD8+ CTL) significantly decreased post-induction (PB ThEff: 28.5±16.4 vs 14.4±10.6, p<0.001; PB CTLEff: 58.6±19.7 vs 39.0±13.9, p=0.005), whereas CTL central memory cell counts increased (PB CTLCM 11.7±11.2 vs, 15.9±11.4 p=0.058). A similar effector to central memory T cell conversion was observed in BM and was more pronounced among CTL (BM CTLEff/CM ratio: 21.6±54.8 vs 2.1±1.6, p= 0.002). Overall response rate on study was 80%, with 53.5% (8/15) achieving ≥VGPR. MRD negativity rate (at 10-5 sensitivity) post-induction was 20% (3/15). The subset of patients who achieved ≥VGPR had higher rates of Th and CTL CM cell differentiation at baseline [≥VGPR vs <VGPR; PB ThEff/CM ratio: median 1.0 (range 0.1 - 1.5) vs 3.1 (0.8 - 212.1); p=0.018; PB CTLEff/CM ratio: median 4.1 (range 0.7 - 16.3) vs 13.2 (4.3 - 10607.1); p=0.056]. Among the MRD negative group, one patient remained in sustained CR at 38 months follow up and retained a high Th/CTL CM conversion rate throughout. At the time of relapse, PB (n=6) and BM (n=2) specimens were collected. While no significant alterations in PB NK cell maturation or activation were observed, circulating CTL Eff / CM distribution reverted to baseline levels (baseline vs relapse; PB CTLEff/CM ratio: 743.6±2755.1 vs 282.7±672.0; p=0.156). BM CTL cell effector / central memory distribution also tends to return to pre-induction levels. Conclusions: Unlike preclinical data where Elo has shown to enhance NK cell activity, longitudinal immune profiling analysis in patients with RRMM treated with Elo-KRd revealed limited activation of NK cell and no effect on NK cell maturation. Instead, we noted several changes within T cell compartment, notably activation and subsequent loss of Th and CTL effector cells, along with gain of central memory phenotype. This observation was most apparent for patients achieving ≥VGPR who exhibited significant higher rate of Effector to CM T cell conversion. On relapse, CM CTL cell frequency in both PB and BM compartments decreased to baseline level. Taken together, our results suggest that higher CM conversion rate, typically associated with sustained antigen stimulation, was associated with response to study treatment. Disclosures Foureau: Cytognos: Honoraria; TeneoBio, Celgene: Research Funding. Bhutani: Amgen, BMS, Takeda: Speakers Bureau; Sanofi: Consultancy; Janssen, MedImmune, Takeda, Celgene, BMS, Cerecor, Celularity: Research Funding. Atrash: GSK: Research Funding; AMGEN: Research Funding; Jansen: Research Funding, Speakers Bureau. Paul: Regeneron: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees; Janssen Pharmaceuticals Inc: Membership on an entity's Board of Directors or advisory committees; Amgen Inc.: Speakers Bureau; Bristol Myers Squibb: Divested equity in a private or publicly-traded company in the past 24 months. Symanowski: Eli Lilly: Consultancy, Other: DSMB Member; Immatics: Consultancy, Other: DSMB Member; Carsgen: Consultancy. Voorhees: Bristol-Myers Squibb Company.: Other: Data Safety & Monitoring; AbbVie Inc, Bristol-Myers Squibb Company; Consulting Agreement: GlaxoSmithKline, Novartis, Oncopeptides: Other: Advisory Committee. Usmani: EdoPharma: Consultancy; Janssen: Consultancy, Research Funding, Speakers Bureau; Amgen: Consultancy, Research Funding, Speakers Bureau; Array BioPharma: Consultancy, Research Funding; Abbvie: Consultancy; GSK: Consultancy, Research Funding; Celgene/BMS: Consultancy, Research Funding, Speakers Bureau; Sanofi: Consultancy, Research Funding, Speakers Bureau; Seattle Genetics: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Merck: Consultancy, Research Funding; Janssen Oncology: Consultancy, Research Funding; Takeda: Consultancy, Research Funding, Speakers Bureau; SkylineDX: Consultancy, Research Funding; Bristol-Myers Squibb: Research Funding.

scholarly journals Phase 1 Study of CD19 Targeted 4-1BBL Costimulatory Agonist to Enhance T Cell (Glofitamab Combination) or NK Cell Effector Function (Obinutuzumab Combination) in Relapsed/Refractory B Cell Lymphoma

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 16-17 ◽  
Author(s):  
Martin Hutchings ◽  
Fritz C. Offner ◽  
Francesc Bosch ◽  
Giuseppe Gritti ◽  
Carmelo Carlo-Stella ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Board Of Directors ◽  
Dose Escalation ◽  
Research Funding ◽  
Bispecific Antibody ◽  
Nk Cell ◽  
Publicly Traded ◽  
Advisory Committees ◽  
Anti Tumor Activity

Background: Up to 50% of patients suffering from Non-Hodgkin`s lymphoma (NHL) become refractory to or relapse after treatment (M. Crump, Blood 2017). With this, the lack of curative outcomes for patients with both indolent and aggressive NHL subtypes remains an unmet medical need. The CD20 CD3 T cell bispecific antibody glofitamab induces specific T-cell activation and has demonstrated significant single agent activity in r/r NHL patients (NP30179 study, M. Dickinson, EHA 2020, Abstract S241). RO7227166, a CD19 targeted 4-1BBL (CD137) costimulatory agonist has shown synergistic anti-tumor activity when combined with glofitamab in preclinical models (fig 1). RO7227166 is a bispecific antibody-like fusion protein composed of a split trimeric 4-1BB ligand, a tumor antigen-targeting moiety recognizing CD19, and a silent Fc part preventing Fc-mediated toxicity. 4-1BB is an inducible co-stimulatory molecule expressed by activated T-cells or NK cells. Through CD19-binding, the 4-1BB ligand moiety can deliver co-stimulatory signals to activated T- and NK-cell subsets in the tumor. The expected mode of action (MoA) for this molecule is to deliver a costimulatory signal 2 to enhance the effector function of tumor-infiltrating T cells or NK cells upon their activation (signal 1) by a T-cell bispecific antibody (e.g. glofitamab, RO7082859) or a tumor-targeted ADCC antibody (e.g. obinutuzumab). By delivering direct T-cell-target cell engagement followed by costimulatory activation the aim is to offer a highly active off-the-shelf immunotherapy combination. Methods: RO7227166 is being developed in combination with glofitamab and obinutuzumab in a phase I, open-label, dose-escalation study BP41072 (NCT04077723). The study is designed to evaluate the combination maximum tolerated dose (MTD), safety, tolerability, pharmacokinetic (PK), and/or pharmacodynamic (PD) profile of escalating doses of RO7227166, and to evaluate preliminary anti-tumor activity in participants with r/r NHL. The dose escalation stage is divided into Part I (combination with obinutuzumab) and Part II (combination with glofitamab) followed by an expansion stage (Part III). During Part I patients receive 1000mg obinutuzumab intravenously (IV) at a q3w schedule in combination with CD19 4-1BBL IV. During part II glofitamab is given in a q3w schedule with RO7227166 introduced at C2D8 and administered concomitantly from C3D1 onwards. A fixed dose of obinutuzumab (Gpt; pre-treatment) is administered seven days prior to the first administration of RO7227166 and seven days prior to the first administration of glofitamab (M. Bacac, Clin Cancer Res 2018; M. Dickinson, EHA 2020, Abstract S241). Patients will initially be recruited into part I of the study only using single-participant cohorts, where a rule-based dose-escalation is implemented, with dosing initiated at 5 μg (flat dose). As doses of RO7227166 increase, multiple participant cohorts will be recruited and dose-escalation will be guided by the mCRM-EWOC design for overdose control. Commencement of Part II including decision on the RO7227166 starting dose will be guided by safety and PK data from Part I. Patients with r/r NHL meeting standard organ function criteria and with adequate blood counts will be eligible. The maximum duration of the study for each participant will be up to 24 months in Part I (excluding survival follow-up) and up to 18 months in Part II and Part III. Tumor biopsies and peripheral blood biomarker analyses will be used to demonstrate MoA and proof of concept of an off the shelf flexible combination option providing signals 1 and 2. Disclosures Hutchings: Takeda: Honoraria; Takeda: Research Funding; Genmab: Honoraria; Roche: Honoraria; Genmab: Research Funding; Janssen: Research Funding; Novartis: Research Funding; Sankyo: Research Funding; Roche: Consultancy; Genmab: Consultancy; Takeda: Consultancy; Roche: Research Funding; Celgene: Research Funding; Daiichi: Research Funding; Sanofi: Research Funding. Bosch:Hoffmann-La Roche: Research Funding. Gritti:Italfarmaco: Consultancy; F. Hoffmann-La Roche Ltd: Honoraria; Jannsen: Other: Travel Support; Autolus: Consultancy; IQVIA: Consultancy; Kite: Consultancy; Takeda: Honoraria; Amgen: Honoraria. Carlo-Stella:Bristol-Myers Squibb, Merck Sharp & Dohme, Janssen Oncology, AstraZeneca: Honoraria; Servier, Novartis, Genenta Science srl, ADC Therapeutics, F. Hoffmann-La Roche, Karyopharm, Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics and Rhizen Pharmaceuticals: Research Funding; Boehringer Ingelheim and Sanofi: Consultancy. Townsend:Roche, Gilead: Consultancy, Honoraria. Morschhauser:Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Servier: Consultancy; Janssen: Honoraria; Epizyme: Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Genentech, Inc.: Consultancy. Cartron:Celgene: Consultancy, Honoraria; F. Hoffmann-La Roche: Consultancy, Honoraria; Sanofi: Honoraria; Abbvie: Honoraria; Jansen: Honoraria; Gilead: Honoraria. Ghesquieres:CELGENE: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Roche: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Gilead: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Janssen: Honoraria. de Guibert:Gilead Sciences: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Herter:Roche Glycart AG: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties. Korfi:Roche Diagnostics GmbH: Consultancy. Craine:Roche: Current Employment. Mycroft:Roche: Current Employment. Whayman:Roche: Current Employment. Mueller:Roche: Current Employment. Dimier:Roche: Current Employment. Moore:Roche: Current Employment. Belli:Roche Pharma: Current Employment. Kornacker:Hoffmann-La Roche Ltd.: Current Employment, Current equity holder in publicly-traded company. Lechner:Roche Diagnostics GmbH: Current Employment, Current equity holder in publicly-traded company. Dickinson:Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; Merck Sharp & Dohme: Consultancy; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

scholarly journals Response to Anti-Bcma CAR T Cell Therapy Correlates with T Cell Exhaustion and Activation Status in T Cells at Baseline in Myeloma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1909-1909 ◽  
Author(s):  
Meng Wang ◽  
Iulian Pruteanu ◽  
Adam D. Cohen ◽  
Alfred L. Garfall ◽  
Lifeng Tian ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
Precursor Cells ◽  
Central Memory ◽  
Advisory Committees ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T

Despite intense efforts, multiple myeloma remains incurable in most patients with the standard of care therapies. The plasma cell surface receptor B cell maturation antigen (BMCA) is highly expressed by myeloma cells and we recently demonstrated that 12 out of 25 heavily pretreated myeloma patients achieved a partial response or better after anti-BCMA CAR T cell treatment (VGPR, n=5; CR, n=1; sCR, n=1; Cohen et al., 2019, JCI 129(6):2210). To better understand the biological basis of this therapy, we identified key correlates of response using the pre-manufacturing apheresed T cells, the infusion product, and post-infusion T cells from the 25 patients in this cohort. As reported before, the disease characteristics, tumor burden, and CAR transduction efficiency did not correlate with therapy response. CAR T cell expansion, measured by the area under the curve of CAR qPCR in the first 21 days (AUC[0-21]), was highest in responding, lowest in non-responding patients (Jonckheere-Terpstra test, JT = 38, p=1.8x10^-6)(Fig.1A,B). Soluble BCMA, a biomarker of disease burden, shows a similar trend with response (Jonckheere-Terpstra test, JT = 54, p=1.2x10^-4). Furthermore, AUC[0-21] for CAR T cell expansion and soluble BCMA decline also strongly correlated (Spearman's rank correlation test, rho=0.82; p=2.41x10^-6), underscoring the quantitative relationship between CAR T cell expansion and tumor reduction. We have previously shown that response to CAR T cell therapy in CLL is largely determined by T cell memory function. To find if this extends to myeloma, we immunophenotyped apheresed T cells (or CAR-T precursor cells) and infusion product from the 25 patients. Phenotypically distinct T cell subpopulations were identified using shared-nearest-neighbor clustering method (PMID: 31178118) and their correlation with response to CAR T cell treatment was evaluated. This analysis revealed that among CD4+ and CD8+ CAR-T precursor cells, subpopulations representing naive and central memory T cells were enriched in T cells from responding patients, while non-responders displayed a distinctly activated effector phenotype at baseline. Additional analyses showed that apheresed CD8+ and CD4+ T cells from responder patients were non-cycling, granzyme B-negative, CTLA4[low] but otherwise largely immune checkpoint inhibitor-negative. CD8+ CAR-T precursor cells isolated from non-responders exhibited high expression levels of TIM3 or LAG3, and/or granzyme B, but not PD1, CTLA4, CD45RO or CD27. These data confirm the high activation, potential exhaustion and end-stage differentiation state of CAR-T precursor cells in this group. Similar analyses of infusion product CAR T cells did not reveal subpopulations associated with response. Clustering analysis of CD8+ CAR T cells within 20 days after infusion revealed a BCMA CAR-expressing cluster enriched in responding patients: a non-cycling, negatively regulated, Eomes-expressing central memory subset (cluster 0; Fig. 1E). Non-responding patients CAR-T cells displayed high levels of granzyme B and PD1 expression but were otherwise devoid of signs of activation (cluster 8; Fig. 1F). Furthermore, the abundance of CD8+ CAR-T cells with cluster 0 and 8 phenotype correlated significantly with in vivo expansion (AUC[0-21]; Fig. 1C). Four patients with a sufficiently high proportion of CAR expressing cells were phenotyped up to 125 days post-infusion. This analysis showed that the highly activated CAR T cell clusters 2 and 5 dominated at early phases post infusion but was rapidly replaced by non-cycling CAR T cells with downregulated CTLA4 and LAG3 but maintained expression of PD1 and TIM3 (cluster 0; Fig. 1D). Patient 27 with VGPR had a prominent effector population four months after infusion. BCMA-redirected CD4+ CAR T cells showed an enrichment of central memory phenotype CAR T cells in responding patients early after infusion, with high expression of Eomes, TIM3, and other immune checkpoint inhibitor molecules. This cluster also dominated the CD4 T cell repertoire in the first four months after infusion in the four responding patients. In conclusion, our data suggest that strategies to promote expression of Eomes and central memory function and reduce exhaustion in BCMA CAR T cells will enhance clinical activity. Further, these results underscore the "self-sustaining" feature of successful CAR T cell therapies in myeloma. Disclosures Pruteanu: Novartis: Employment. Cohen:Poseida Therapeutics, Inc.: Research Funding. Garfall:Tmunity: Honoraria, Research Funding; Amgen: Research Funding; Novartis: Patents & Royalties: inventor on patents related to tisagenlecleucel (CTL019) and CART-BCMA, Research Funding; Janssen: Research Funding; Surface Oncology: Consultancy. Lacey:Novartis: Patents & Royalties: Patents related to CAR T cell biomarkers; Tmunity: Research Funding; Novartis: Research Funding. Fraietta:Tmunity: Research Funding; Cabaletta: Research Funding; LEK Consulting: Consultancy. Brogdon:Novartis: Employment. Davis:Tmunity: Research Funding; Cabaletta: Research Funding. Levine:Tmunity Therapeutics: Equity Ownership; Avectas: Membership on an entity's Board of Directors or advisory committees; Vycellix: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy; Novartis: Consultancy, Patents & Royalties, Research Funding; Cure Genetics: Consultancy; Incysus: Membership on an entity's Board of Directors or advisory committees; Brammer Bio: Membership on an entity's Board of Directors or advisory committees; CRC Oncology: Consultancy. Milone:Novartis: Research Funding; Novartis: Patents & Royalties: patents related to tisagenlecleucel (CTL019) and CART-BCMA. Stadtmauer:Janssen: Consultancy; Tmunity: Research Funding; Amgen: Consultancy; Abbvie: Research Funding; Novartis: Consultancy, Research Funding; Takeda: Consultancy; Celgene: Consultancy. June:Novartis: Research Funding; Tmunity: Other: scientific founder, for which he has founders stock but no income, Patents & Royalties. Melenhorst:National Institutes of Health: Research Funding; Parker Institute for Cancer Immunotherapy: Research Funding; Novartis: Research Funding, Speakers Bureau; Colorado Clinical and Translational Sciences Institute: Membership on an entity's Board of Directors or advisory committees; Stand Up to Cancer: Research Funding; Incyte: Research Funding; IASO Biotherapeutics, Co: Consultancy; Simcere of America, Inc: Consultancy; Shanghai Unicar Therapy, Co: Consultancy; Genentech: Speakers Bureau.

scholarly journals A Phase 2 Study of Panobinostat (PAN) in Combination with Bortezomib (BTZ) in Patients with Relapsed/Refractory Peripheral T-Cell Lymphoma (PTCL) or NK/T-Cell Lymphoma (NKL)

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 503-503 ◽  
Author(s):  
Yeow-Tee Goh ◽  
William YK Hwang ◽  
Colin Phipps Diong ◽  
Yap chun Hsien ◽  
Kevin Tay ◽  
...  
Keyword(s):  
T Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
Nk Cell ◽  
Cell Lymphoma ◽  
Performance Status ◽  
Objective Response ◽  
T Cell Lymphoma ◽  
Conventional Chemotherapy ◽  
Advisory Committees

Abstract Background Relapsed/refractory PTCL and NKL after conventional chemotherapy carry a poor prognosis and there is currently no proven salvage treatment available. Numerous preclinical studies have demonstrated synergistic interactions between proteasome and histone deacetylase (HDAC) inhibitors. PAN inhibits the aggresome pathway of protein degradation, which is upregulated when the proteasome pathway is inhibited by BTZ. Primary end point of this phase II multi-center open-label clinical study (NCT00901147) is the objective response rate (ORR) according to the Revised Response Criteria (Cheson 2007) among eligible patients (pts) treated with this novel combination of BTZ and PAN. Secondary end points include the evaluation of the progression-free survival (PFS) and the assessment of the safety and tolerability of the combination. We report the final clinical results of our study exploring this novel combination. Methods Pts with histologically confirmed PTCL or NKL who failed or were refractory to 1 or more prior systemic therapy, and had measurable disease and ECOG performance status 0–2 were eligible. Pts were accrued according to a 2-stage Gehan design. Pts receive thrice weekly oral PAN (20 mg) and twice weekly BTZ (IV 1.3 mg/m2), both for 2 of 3 weeks for up to 8 cycles. CT scanning and/or FDG-PET were performed after every two cycles. Results: Among 25 pts enrolled, histologies included: angioimmunoblastic T-cell lymphoma (AITL) n=8, PTCL (unspecified) n=11, Anaplastic large cell lymphoma, ALK+ and ALK- n=1 and 2 respectively, NKL, nasal type n=2 and subcutaneous panniculitis-like T-cell lymphoma n=1. The median age was 59 (35-79) years, and 64% were male. Outcomes are available on 23 patients as 2 patients withdrew consent before any response assessment could be made. The ORR (CR+PR) was 43% (10/23) with 22% (5/23) attaining a CR. Median time to response was 6 weeks. Five pts (22%) had stable disease while 8 pts developed progressive disease (35%) while on study. Pts received a median of 2 prior therapies (range 1-4); 28% had prior autologous stem cell transplantation (SCT). Common treatment-related grade 3/4 adverse events included thrombocytopenia (68%), neutropenia (36%), diarrhoea (28%) and asthenia/fatigue (16%). Peripheral neuropathy of any grade was observed in 40%. 5 pts successfully underwent subsequent allogeneic SCT. Updated survival analysis will be presented. Conclusions The study regimen is generally well tolerated and shows encouraging activity across different T/NK-cell lymphomas. The novel combination could successfully serve as a bridge to allogeneic SCT for many transplant-eligible patients who have failed conventional chemotherapy. These results form the basis for further validation studies on proteasome and HDAC inhibition in PTCL or NKL. Ongoing correlative studies are designed to determine if the study regimen is more active in diseases with up-regulation of NF-kappa B activity or transcription factors/ co-regulators known to be modified by acetylation. Disclosures Goh: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Jannsen Pharmaceuticals: Honoraria, Research Funding, Speakers Bureau; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead Sciences: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees. Kim:Novartis, Celgene, Takeda: Research Funding. Tan:JANSEN: Honoraria, Research Funding; NOVARTIS: Research Funding.

scholarly journals Preliminary Clinical Data from a Phase 1 Trial with CPI-818, a Selective ITK Inhibitor That Preferentially Blocks the Growth of T Lymphoma Cells

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1571-1571
Author(s):  
Patrick P. Ng ◽  
Mehrdad Mobasher ◽  
Kitman S. Yeung ◽  
Andrew N. Hotson ◽  
Craig M. Hill ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Nk Cells ◽  
Board Of Directors ◽  
Research Funding ◽  
Nk Cell ◽  
Phase 1 ◽  
Employment Equity ◽  
Advisory Committees ◽  
Equity Ownership

Introduction ITK is a tyrosine kinase critical to T cell receptor (TCR) signaling. Overexpression of this gene has been reported in cutaneous T-cell lymphoma (CTCL) and peripheral T-cell lymphoma (PTCL). Genomic analyses have demonstrated the contribution of aberrant TCR signaling in the pathogenesis of T-cell lymphomas (TCL). RLK, a closely related kinase, is co-expressed with ITK in T and NK cells, and is partially functionally redundant with ITK signaling. In NK cells, ITK has been shown to be involved in FcγRIII signaling and antibody-dependent cellular cytotoxicity (ADCC). However, the relative contribution of ITK vs RLK in ADCC is not well understood. Thus, selective inhibition of ITK, but not other signal transduction components such as RLK, may be an effective strategy to treat TCL while preserving normal T and NK cell functions. CPI-818 is an orally bioavailable, covalent inhibitor of ITK with >100-fold selectivity over RLK and BTK. It was well tolerated and exhibited anti-tumor activity in companion dogs with spontaneous TCL (2019 AACR Annual Meeting Abstract #1313). A phase 1/1b trial with CPI-818 in human TCL has been initiated (NCT03952078). Here we present preclinical evidence that CPI-818 inhibits the proliferation of human malignant T cells with relative sparing of normal lymphocytes and report early results from the clinical trial. Methods Eligible patients for the dose-escalation/expansion trial of CPI-818 have relapsed/refractory TCL (PTCL, CTCL and others). Starting dose of CPI-818 is 100 mg BID continuously. The objectives of the study are to evaluate the safety and tolerability of CPI-818 in ascending dose levels; evaluate pharmacokinetics/pharmacodynamics and potential biomarkers. In in vitro studies, T cells from the blood of Sézary syndrome patients were stimulated for 6 days with αCD3/CD28. Sézary cells were identified by antibodies to specific TCR Vβ. For assays of ADCC, αCD20-coated lymphoma B cells were cultured with NK cells from multiple healthy donors for 18 h with inhibitors. In animal studies, mice received control or CPI-818-formulated diet (300 mg/kg/day). C57BL/6 mice were vaccinated with keyhole limpet hemocyanin (KLH) or subcutaneously implanted with the TCL line EL4. MRL/lpr mice began treatment at 9 weeks old. Lymph nodes were calipered weekly. Spleens and lungs were harvested at 22 weeks. Results Mouse models were studied to assess the impact of CPI-818 on normal, autoreactive and malignant T cells in vivo. No changes in total blood cell counts or T, B, NK cell subsets in lymphoid organs were seen in normal mice receiving daily doses of CPI-818 sufficient to continuously inhibit ITK for 28 days. Immune responses to antigen re-challenge were not affected in these mice, as determined by levels of antibody or CD4 T cell response to vaccination with KLH. In mice with established EL4 lymphoma, administration of CPI-818 reduced the growth of tumors at the primary site and in the draining lymph nodes (P values <0.033). CPI-818 also reduced lymphadenopathy and expansion of autoreactive T cells in the spleens of MRL/lpr mice (P values <0.0001), without affecting CD4 or CD8 cells. Sézary cells from 3 of 3 patients tested in vitro were more sensitive to growth inhibition with CPI-818 than autologous normal CD4 or CD8 cells, or T cells from a healthy donor (Figure 1). CPI-818 showed minimal inhibition of NK-mediated ADCC (5%), whereas CP-2193, an ITK/RLK dual inhibitor with an IC50 for ITK comparable to CPI-818, reduced ADCC by 50%. CPI-818 has been administered to two patients at the first dose level cohort (100 mg BID) with no DLTs, and with no changes to B, T, and NK cell counts in blood during the first dosing cycle (21 days). Pharmacokinetic and occupancy studies have revealed 80% and 50% occupancy of ITK at peak and trough drug levels, respectively in peripheral blood T cells. Conclusions CPI-818 is a selective covalent ITK inhibitor that has greater antiproliferative effects on malignant and autoreactive T cells compared to normal T cells. The drug has a minimal impact on NK mediated ADCC compared with a less selective inhibitor that also blocks RLK. Preliminary data from a phase 1/1b study shows CPI-818 at 100 mg BID was tolerable with acceptable bioavailability and ITK occupancy. Further dose escalation is ongoing. Disclosures Ng: Corvus Pharmaceuticals, Inc.: Employment, Equity Ownership. Mobasher:Corvus Pharmaceuticals: Employment, Equity Ownership. Yeung:Corvus Pharmaceuticals: Employment, Equity Ownership. Hotson:Corvus Pharmaceuticals: Employment, Equity Ownership. Hill:Corvus Pharmaceuticals: Employment, Equity Ownership. Madriaga:Corvus Pharmaceuticals: Employment, Equity Ownership. Dao-Pick:Corvus Pharmaceuticals: Employment, Equity Ownership. Verner:Corvus Pharmaceuticals: Employment, Equity Ownership. Radeski:Corvus Pharmaceuticals: Research Funding. Khodadoust:Corvus Pharmaceuticals: Research Funding. Kim:Innate Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Eisai: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kyowa Hakko Kirin: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; Horizon: Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Galderma: Research Funding; Elorac: Research Funding; Soligenix: Research Funding; Medivir: Honoraria, Membership on an entity's Board of Directors or advisory committees; miRagen: Research Funding; Forty Seven Inc: Research Funding; Neumedicine: Research Funding; Portola Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Corvus: Honoraria, Membership on an entity's Board of Directors or advisory committees; Trillium: Research Funding. Miller:Corvus Pharmaceuticals: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Buggy:Corvus Pharmaceuticals: Employment, Equity Ownership. Janc:Corvus Pharmaceuticals: Employment, Equity Ownership.

scholarly journals Romidepsin in Conditioning and Maintenance Mitigates Relapse Risk and Enhances NK-Cell Cytotoxicity in Patients Receiving Allogeneic Stem Cell Transplant for Aggressive T-Cell Malignancies: Results of a Phase I/II Clinical Trial

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 553-553
Author(s):  
Chitra Hosing ◽  
Zachary Braunstein ◽  
Alaa M Ali ◽  
Benigno C. Valdez ◽  
Borje S. Andersson ◽  
...  
Keyword(s):  
Clinical Trial ◽  
T Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
Nk Cell ◽  
Advisory Committees ◽  
Nk Cell Cytotoxicity ◽  
T Cell Malignancies ◽  
Nk Cytotoxicity ◽  
Relapse Rates

Abstract Background: Allo-SCT is the only curative option for patients with high risk and relapsed/refractory T-cell malignancies. Even among allo-SCT recipients, survival is less than 50% and relapse rates are 55-60%. We developed a clinical trial to decrease relapse after allo-SCT for these patients using romidepsin (rom), a histone deacetylase inhibitor approved for the treatment of relapsed T-cell lymphomas. Based on pre-clinical data demonstrating enhanced and synergistic cell killing with the addition of rom to busulfan (Bu) and fludarabine (Flu) in malignant T-cells, we created a novel transplant regimen (BuFluRom). We hypothesized this regimen, coupled with maintenance rom (m-rom), would enhance malignant T-cell killing, eradicate MRD at transplant, decrease relapse, and stimulate the GVL effect by stimulating NK-cells. Here we present results of this clinical trial, with correlative data evaluating NK-cytotoxicity. This is the first trial designed specifically to treat T-cell malignancies with allo-SCT. (NCT02512497) Methods: This is a phase I/II clinical trial. Eligible patients had: a diagnosis of T-cell leukemia (including T-acute lymphoblastic leukemia) or T-cell lymphoma (cutaneous or peripheral) in at least a partial remission requiring an allo-SCT, <70 years of age, with a matched sibling/unrelated donor. The primary objective was to determine the recommended phase 2 dose (RP2D) of rom from 3 dose levels (1, 2, 3 mg/m2) when combined with BuFlu (AUC 20000 or 16000, Figure). Patients received standard tacrolimus/methotrexate GVHD prophylaxis with ATG for MUDs. Once RP2D was determined, an expansion cohort of up to 30 patients (total) was included. M-rom was initiated between day +28 and +100 for 1 year (2 years max). The effect of rom on NK-cell cytotoxicity was assessed on samples taken pre-transplant, and 1, 3, 6, 12 months post allo-SCT. NK cytotoxicity was assessed by isolating mononuclear cells from patient samples and targeting them against K562 and T-cell lymphoma targets using the calcein-AM assay. Fine-Gray models were used to estimate PFS, OS, and cumulative incidence, and compare survival curves across groups. Results: 21 patients have been enrolled (Table). One DLT was observed (VOD), at dose level 2, and the RP2D of rom in conditioning was determined to be 2 mg/m2. With a median follow-up time of 10.1 months, the median OS has not been reached (3.3-NR months), with a 1 and 3-year OS probability of 62.8% & 55.8%. The median PFS is 28.2 months (3.8-28.1), with 1 and 3 year PFS of 57% & 30.4%. Cumulative incidence (CI) of NRM at day 100 and 1 year were 14.8% and 20%. CI of grade II-IV aGHVD and extensive cGVHD were 47.6% and 18.5%. The CI of relapse (CIR) was 22.8% at 1 year (95% CI 6.6-44.9%). There was no difference between PFS among patients with MRD versus those without MRD prior to transplant (p=0.96), and no difference in 1-year CIR (p=0.9). PFS and CIR at 1 year was substantially better in the lymphoma than leukemia patients (85.7% vs 44%, p=0.049), and (0% vs 32.1%, p=0.05). No patients with PTCL relapsed, and 3/5 patients with T-PLL are alive, disease free. 13/21 (62%) of patients received m-rom with a median number of 10 cycles (range 1-41). (Table) 7 patients experienced grade 3/4 adverse events (AE), though no patients discontinued m-rom due to toxicity. NK-cytotoxicity was higher at each time point in patients who received m-rom compared to those who did not, though there were insufficient patients to reach statistical significance. When NK-cytotoxicity was assessed between the two groups after starting maintenance, NK-cytotoxicity in the m-rom group was significantly higher than in those without m-rom (p=0.05) (Figure). Conclusions: BuFluRom with m-rom is effective at decreasing relapse in patients with T-cell malignancies, with 1-year CI relapse below expected relapse rates for this set of diseases. Toxicities were similar to standard BuFlu alone and the RP2D of rom in conditioning was established at 2 m g/m2. Intriguingly, BuFluRom mitigated the poor outcomes of patients with MRD prior to transplant. Further, early data suggests m-rom enhances NK-cell cytotoxicity post allo-SCT, potentially augmenting the GVL effect and accounting for decreased relapse rates. Long-term follow-up is needed to evaluate these results, but these results suggest the BuFluRom regimen with m-rom could become a new option for patients receiving allo-SCT for T-cell malignancies to mitigate relapse. Figure 1 Figure 1. Disclosures Hosing: Nkarta Therapeutics: Membership on an entity's Board of Directors or advisory committees. Popat: Bayer: Research Funding; Abbvie: Research Funding; Novartis: Research Funding; Incyte: Research Funding. Vasu: Boehringer Ingelheim: Other: Travel support; Seattle Genetics: Other: travel support; Kiadis, Inc.: Research Funding; Omeros, Inc.: Membership on an entity's Board of Directors or advisory committees. de Lima: Miltenyi Biotec: Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees. William: Dova Pharmaceuticals: Research Funding; Incyte: Research Funding; Kyowa Kirin: Consultancy; Merck: Research Funding; Guidepoint Global: Consultancy. Lee: Kiadis Pharma: Divested equity in a private or publicly-traded company in the past 24 months, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Courier Therapeutics: Current holder of individual stocks in a privately-held company. Brammer: Kymera Therapeutics: Consultancy; Celgene: Research Funding; Seattle Genetics: Speakers Bureau.

scholarly journals The Relationship between Baseline Biomarkers and Efficacy of Isatuximab in Combination with Pomalidomide and Dexamethasone in RRMM: Insights from Phase 1 and Phase 3 Studies

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3179-3179
Author(s):  
Paul G. Richardson ◽  
Joseph Mikhael ◽  
Thierry Facon ◽  
William I. Bensinger ◽  
Sandrine Macé ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
Nk Cell ◽  
Phase 1 ◽  
Phase 3 ◽  
Advisory Committees ◽  
Blood Samples ◽  
Bone Marrow Plasma

Background: Anti-CD38 monoclonal antibody therapy has become an integral component of treatment for relapsed/refractory multiple myeloma (RRMM) but not all patients respond. Identification of predictive biomarkers could help clinicians identify the best treatment course for a patient. We present baseline biomarker analyses on samples from a Phase 1 (Study 1; NCT02283775) and Phase 3 (Study 2; NCT02990338 [ICARIA-MM]) clinical study that evaluated the addition of isatuximab (Isa), an anti-CD38 monoclonal antibody, to pomalidomide and dexamethasone (Pd) for the treatment of RRMM. CD38 receptor density (RD), FCGR3A (Fc immunoglobulin receptor) genotype, and bone marrow or peripheral blood immunophenotyping were evaluated as potential predictive biomarkers for a response to the Isa-Pd regimen. Methods: Both studies enrolled similar patient populations with RRMM who had received ≥2 prior lines of therapy including lenalidomide and a proteasome inhibitor. Baseline blood samples were taken prior to first treatment in both studies; in addition, a bone marrow sample was taken during screening in Study 1. In Study 1, bone marrow plasma cells were analyzed for CD38 RD. Immune cell populations (CD19+ B-cell, CD3+ T-cell, CD4+ T-cell, regulatory T-cells (Tregs) and natural killer (NK) cells [CD56+ bright CD16+ low subset and CD56+ dim CD16+ bright subset]) were characterized using blood samples and bone marrow aspirates. Blood samples from both studies were analyzed for FCGR3A genotyping (V158 and F158 high- and low-affinity alleles). Biomarker results were correlated with response, defined as at least partial response according to IMWG criteria. Results: Study 1 enrolled and treated 45 patients with Isa-Pd. Study 2 randomized 154 patients to Isa-Pd and 153 patients to Pd. Baseline patient demographics were similar for both studies and the median number of prior lines of therapy was 3 (range: 1-10) for Study 1 and 3 (2-11) for Study 2. The overall response rates (ORR) with Isa-Pd were 62.2% (28/45) in Study 1 and 60.4% (93/154) in Study 2. In Study 1, the median CD38 RD, for 31 patients with evaluable results, was 108,172 receptors/cancer cell (range: 12,950-337,335). In patients responding to Isa-Pd (n=21), the median CD38 RD value was 120,931 (48,770-337,335) receptors/cancer cell; in patients not responding to Isa-Pd (n=10), the median CD38 RD value was 85,370 (range 12,950-309,003) receptors/cancer cell. Univariate analysis in Study 1 showed no association between CD38 RD and ORR (p=0.2870). Across five Phase 1/2 clinical studies with Isa, 4/198 patients (2.0%) had a CD38 RD level below 48770, the lowest value in a responder patient. FCGR3A genotyping results were available for both studies. Across both studies, the distribution of the F158V single nucleotide polymorphism of FCGR3A gene was 42% for F/F, 42% for F/V and 16% for V/V. In both studies, responses were observed for all 3 genotypes (Table 1). In Study 1, the observed ORRs with the Isa-Pd regimen for the 3 genotypes ranged from 50.0% to 80.0%, whereas in the larger Phase 3 Study 2, the ORR was more similar across genotypes (range 56.9% to 65.5%). Median progression-free survival (PFS) ranged from 8.97 months to 14.78 months and Isa-Pd showed a PFS benefit vs Pd for all 3 genotypes (Table 1). In Study 1, 42 patients had at least one baseline peripheral blood immune biomarker value; of these, 17 patients were non-responders and 25 patients were responders. In addition, 41 patients had at least one baseline bone marrow immune biomarker measurement (16 were non-responders and 25 were responders). No significant difference was observed between responders and non-responders for the tested immune biomarkers in bone marrow during screening. P-values were 0.2817 (CD19+ B-cell), 0.6446 (CD3+ T-cell), 0.7780 (CD4+ T-cell), 0.1620 (Tregs), 0.9591 (NK cell), 0.8275 (CD56+ bright/CD16+ low NK cell), and 0.7389 (CD56+ dim/CD16+ bright NK cell). Similarly, there was no significant difference between responders and non-responders for the immune biomarkers in baseline blood samples. Conclusion: Biomarker analyses on samples from patients treated with Isa-Pd did not find a significant association between tumor response and baseline bone marrow plasma cell CD38 RD, FCGR3A genotype, or immunophenotypes in bone marrow plasma cells or peripheral blood. These results suggest there is no benefit in prescreening patients for these parameters before treatment with Isa-Pd. Disclosures Richardson: Karyopharm: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Research Funding. Facon:Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Bensinger:Sanofi, Seattle Genetics, Merck, Karyopharm: Other: Grant; Amgen, Celgene: Other: Personal Fees, Research Funding, Speakers Bureau; Takeda, Janssen: Speakers Bureau. Macé:Sanofi: Employment. Chiron:Sanofi: Employment. van de Velde:Sanofi: Employment. Campana:Sanofi: Employment. Liu:Sanofi: Employment. OffLabel Disclosure: Isatuximab is an investigational agent and has not been approved by the US Food and Drug Administration or any other regulatory agency worldwide for the uses under investigation.

scholarly journals Literature Review of All Cases of Aggressive T-Cell Large Granular Lymphocytic Leukemia Cases and Report of an Additional Case

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5421-5421
Author(s):  
Vanessa Brunet ◽  
Michel Pavic ◽  
Sofia Marouan ◽  
Isabelle Fleury ◽  
Jean-Francois Castilloux
Keyword(s):  
T Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
Lymphoproliferative Disorder ◽  
Clinical Presentation ◽  
Nk Cell ◽  
Leukemic Cells ◽  
Cell Leukemia ◽  
Advisory Committees ◽  
Lgl Leukemia

Abstract Large granular lymphocyte (LGL) leukemia is a spectrum of rare lymphoproliferative disorders, classified into T-cell LGL leukemia, chronic lymphoproliferative disorder of NK-cells and aggressive NK-cell leukemia; chronic NK-cell leukemia is a provisional diagnosis. However, we identified fourteen cases of aggressive T-LGL leukemia retrieved in the literature. Considering this unusual and rare clinical presentation, we are reporting a literature review and presenting an additional case. Leukemic cells of T-LGL leukemia have a characteristic phenotype (CD3+CD8+CD16+CD57+) and show clonal TCR gene rearrangement, while leukemic cells of aggressive NK cell leukemia show a distinguishable phenotype (CD3-CD4-CD8-CD16+CD56+CD57-) and are EBV-related. In contrast with the aggressive NK cell leukemia, the chronic lymphoproliferative disorder of T-cell is not EBV-associated and has a distinguishable immunophenotype (CD16+CD56−CD57+). While T-LGL leukemia and chronic lymphoproliferative disorder of NK-cells have a more chronic disease (years), mainly reported with autoimmune disease (rheumatoid arthritis), numerous infections due to neutropenia and a mild-to-moderate splenomegaly, aggressive NK-cell leukemia is characterized by systemic manifestations and a disseminated disease after a few weeks of presentation despite treatment instauration. In contrast to the T-LGL leukemia, aggressive T-LGL leukemia has a clinical presentation similar to the aggressive NK-cell leukemia, characterized by constitutional symptoms, rapidly progressive hepatosplenomegaly, cytopenia and organ infiltration. The atypical clinical presentation and pathological findings of the aggressive T-LGL leukemia explain the diagnostic challenge of this entity for clinicians. In fact, cases of aggressive T- LGL leukemia retrieved atypical size, irregular nuclei and atypical immunophenotype. Some cases had features similar to those described for patients with NK-cell leukemia (CD56+CD57-) while others did not present neither NK nor T-cell classical immunophenotype (CD56-57-). Facing the heterogeneity of aggressive LGL leukemia, the rapidly evolutive disease (multi-organic infiltration) and the absence of randomized trials on large numbers of patients, no consensus on the treatment approach exists. (Table 1) Our patient presented, at the age of 24 yo, with transitory and autonomous resolution of hepatosplenomegaly and pancytopenia. Almost 30 years later, the patient developed a similar and persistent episode, which lead to a diagnosis of aggressive T-cell LGL leukemia. Was this first episode the early and indolent presentation of his T- LGL leukemia or was it only related to an indolent and transitory etiology? Considering the clinical evolution of previously reported case and of our patient, LGL leukemia tends to evolve in many ways; resolution, indolent and chronic or aggressive evolution and transformation into a lymphoma. As the cases retrieved in literature, the diagnosis of our patient was complicated by atypical clinical presentation and unusual pathological findings; massive medullary involvement without real images of intra-sinusal lymphocytosis and atypical T- LGL based on their small-medium size with slightly irregular nuclei and the lack of expression of CD56/CD57. Facing the heterogeneity of treatments attempted for aggressive T-LGL leukemia and their unpredictable response, we believe that the treatments given to our patient were consistent with the current literature and did not add an additional mortality risk (3 cycles of CHOP, 4 cycles of ESHAP, methotrexate, splenectomy). As reported in literature, even though our patient was treated with varying regimens, his disease rapidly evolved into a multi-organic infiltration (skin, lungs, liver, kidney, facial cranial nerves, conus medullaris and bone marrow involvement) Large granular lymphocyte (LGL) leukemia represent a spectrum of indolent and aggressive diseases, whereby an indolent form can evolve into an aggressive form. Aggressive T-cell LGL leukemia are characterized by a multisystem disease, an atypical immunophenotype (CD56-CD57- or CD56+CD57-) and are associated with an uncertainty regarding therapeutics.Our case report of an aggressive T-cell LGL leukemia adds to the few available studies on the subject. Disclosures Pavic: Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

scholarly journals Polyclonal Immune Response in T-LGL Leads to Clonal Expansions Preceding Occurrence of STAT3 Mutations Further Solidifying Clonal Dominance

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 516-516
Author(s):  
Cassandra M. Hirsch ◽  
Michael Clemente ◽  
Peter Chomczynski ◽  
Bartlomiej P. Przychodzen ◽  
Yasunobu Nagata ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
Response Assessment ◽  
Clonal Expansion ◽  
Cytotoxic T Cell ◽  
Advisory Committees ◽  
Treatment Regimens ◽  
Initial Sampling

Abstract T cell large granular lymphocyte leukemia (T-LGLL) characterized by excessive clonal cytotoxic T cell proliferation, is often accompanied by cytopenias and is thought to result from immune-mediated suppression, either by misguided immune antigenic recognition or mimicry triggered by auto-, tumor or viral antigens. Irrespective of the mode of evolution, T-LGLL progresses via: i) purely reactive clonal outgrowth in the context of a polyclonal immune response or: ii) a transforming event such as a STAT3 mutation (STAT3MT) within the immunodominant clone. Studies of TCR rearrangement using DNA based NGS of the TCR Vβ complementarity-determining region 3 (TCR VB CDR3) facilitate analyses of T cell clonality, as the CDR3-based "biological barcodes" allow for clonal quantification. We used serial CDR3 clonotyping accompanied by clonal STAT3 mutant burden measurements to recapitulate the pathological cascade in the course of T-LGLL. We asked if a polyclonal/oligoclonal immune response is the primary process that is clonally "imprinted" by STAT3MT, which would likely arise with the most proliferative clone. We were interested in the dynamics of underlying clonal behavior during treatment. Our initial cohort included 207 well characterized LGL patients. Most presented with anemia (46%), and/or neutropenia (46%). VB expansion was present in 94% of cases, with an average LGL count of 2317k/uL .STAT3MT were found by targeted deep sequencing in 38% of patients in 4 common hotspots: 42% Y640F, 34% D661Y, 11% D661V, and 8% N647I, with an average clonal burden of 28%. Multiple STAT3MT variants were found in some patients. From this cohort, serial samples obtained at presentation and throughout clinical course were obtained from 20 representative cases (10 STAT3MT and 10 STAT3WT), and subjected to analysis of clonal dynamics, including simultaneous deep TCR VB and STAT3 NGS. Patients were sequenced at an average of 4 time points (range 2-8). At least one major clonotype was identified in all patients, and multiple major clonotypes were identified in half. Analyses of clonal architecture revealed that STAT3 clones arose with VB expanded clones. In all cases, the TCR clonal burden was greater than that of STAT3MT demonstrating for the first time that STAT3MT is not the ancestral event for clonal expansion; rather, it evolves within the pre-expanded immunodominant clone. More than half of the patients were treated with immunosuppressive therapy (IST) achieving an approximate 40% response rate. Distinct patterns of clonal dynamics were seen following treatment (see Figure). In some patients, both the STAT3 (if present) and the major TCR clone decreased upon successful therapy. A correlation between a specific IST treatment and a clonal burden decrease was not found. In a subset of patients, the clones persisted despite a hematologic response, suggesting the major clonotype was functionally silenced. We also observed a common phenomenon of TCR "clonotype switching", whereby therapy contracts one major clonotype, while another previously "minor" clonotype emerges. These newly expanded clones did not harbor STAT3MT, and most patients with "switching" were resistant to IST therapy. Multiple clonotypes were present at initial sampling in a few patients without STAT3MT and persisted at the same rate in subsequent samplings, precluding identification of a clear immunodominant clonotype. A stable or increasing clonal burden of both STAT3MT and VB CDR3 was seen in IST non-responders. In sum, STAT3MT were found to be a secondary event to the clonal expansion of the TCR VB clonotype, as a response within an already expanded clonotype and not the initiator of clonal expansion. The dynamics of both the STAT3MT and the TCR VB clonotype can be assessed over disease course and treatment regimens and demonstrate additional clinical ultility when applied to larger prospective clinical trials. The difficulty in finding a direct correlation between response to specific IST and a decrease in TCR VB clonal burden may be due to variable time frames between samplings, heterogeneity of IST regimens and response assessment, or large asymptomatic clonotypes. Prior to this study, the association of remission and elimination of immunodominant clonotypes was unclear. Our results suggest that clonal elimination is not necessary for complete clinical response; rather, the clone can be contracted to a manageable clonal burden or silenced. Disclosures Mustjoki: Novartis: Honoraria, Research Funding; Celgene: Honoraria; Bristol-Myers Squibb: Honoraria, Research Funding; Ariad: Research Funding; Pfizer: Honoraria, Research Funding. Sekeres:Opsona: Membership on an entity's Board of Directors or advisory committees; Opsona: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Maciejewski:Ra Pharmaceuticals, Inc: Consultancy; Apellis Pharmaceuticals: Consultancy; Alexion Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Apellis Pharmaceuticals: Consultancy; Alexion Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Ra Pharmaceuticals, Inc: Consultancy.

scholarly journals Manufacture and Immunological Characterization of GMP-Compliant Functional Sars-COV-2 Cytotoxic T Lymphocytes (CTLs) Utilizing the Clinimacs ® Cytokine Capture System

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 476-476
Author(s):  
Yaya Chu ◽  
Jordan Milner ◽  
Margaret Lamb ◽  
Elena Maryamchik ◽  
Olivia Rigot ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
T Cells ◽  
T Cell ◽  
Board Of Directors ◽  
Cd8 T Cells ◽  
Research Funding ◽  
Cytotoxic T Cell ◽  
Advisory Committees ◽  
Ifn Γ

Abstract Background: The coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a pandemic that has taken millions of lives around the globe. Treatment of patients with moderate and severe COVID-19 disease has included dexamethasone, tocilizumab, Remdesivir, convalescent plasma, and targeted antibodies, however, currently, there are no FDA approved targeted cellular therapies in the treatment of mild or moderate SARS-CoV-2 disease. Virus-specific cytotoxic T cell lymphocytes (vCTLs) have shown therapeutic efficacy in immunocompromised patients with viral infections. We developed a multicenter and multidisciplinary Viral Cytotoxic T-Cell Consortium (VIRCTLC) to investigate the use of vCTLs manufactured by direct enrichment using the Cytokine Capture System (CCS) on the CliniMACS® Prodigy device. SARS-CoV-2 specific PepTivator Peptides consist of overlapping peptides that span the entire sequence of the protein (Protein N and M), or the length of its immunodominant domain (Protein S). The peptides can bind to either MHC class I or MHC class II molecules and are therefore able to target both CD4 and CD8 T cells. Objective: To screen, manufacture, and characterize SARS-CoV-2 vCTLs generated from convalescent COVID-19 donors using the CliniMACS® Cytokine Capture System on the CliniMACS® Prodigy device. Methods: Donor screening was done utilizing PBMNCs from 15 convalescent COVID-19 donors after informed consent. PBMNCs were stimulated with a mix of PepTivator peptides (Miltenyi Biotech®) contained in the S, M and N proteins. IFN-γ levels were examined in CD3, CD4, and CD8 T cells by flow cytometry analysis. After informed consent, PBMNCs from three convalescent COVID-19 donors who screened positively to the PepTivator® peptide pools of SARS-CoV-2 Proteins M, N and S were collected by apheresis using the SPECTRA Optia® apheresis instrument. PBMNCs were incubated with the PepTivator® peptide pools for 4 hours. After incubation, the SARS-CoV-2 vCTLs were enriched using the CliniMACS Cytokine Capture System as we have previously described (Flower/Cairo, et al, ASTCT, 2020). Samples were taken from the enriched vCTLs and tested in gram stains, sterility cultures, cell counts, viability and IFN-γ cytokine staining (CD3/CD4/CD8/IFN-γ marker panel) by flow cytometry. Amplification and sequencing of TCRβ CDR3 regions of pre-stimulated PBMNC, stimulated PBMNCs samples taken from the QC bag (QC samples) and the enriched SARS-CoV-2 vCTLs were performed on the ImmunoSEQ platform using ImmunoSEQ® TCRB Assay kit (Adaptive Biotechnologies, Seattle, WA, USA). Characterization of immune subsets was done by mass cytometry analysis with 41 Immunophenotypic markers. Transcriptome of the immune landscape of QC samples, and enriched vCTLs was compared with the pre samples using the human nCounter PanCancer Immune Profiling Panel on the nCounter system. Results: We demonstrate that 93.3% of convalescent donor blood samples passed the screening criteria for clinical manufacture. Three validation runs resulted in enriched T cells that consisted of 79% + 21% (mean + SEM) IFNγ + T cells (Fig.1). TCRβ sequencing showed that convalescent COVID-19 donors have a highly diverse TCR repertoire and we identified TCRβ CDR3 clones that are known to be associated with SARS-CoV-2 T cell responses. Immunophenotyping analysis demonstrated more CD4 T cells than CD8 T cells in the SARS CoV-2 vCTLs, an increase in memory CD8 and CD4 cells, especially CD8 T EM, CD4 T cm and CD4 T EMRA cells (Fig.2) and an increase DC cells in the SARS CoV-2 vCTL products as compared to pre-stimulated PBMNCs. Expression of the exhaustion markers was not enhanced in the SARS CoV-2 vCTLs as compared to pre-stimulated PBMNCs. Transcriptome analysis showed increased gene expression in T-cell function, interleukin, pathogen defense, and TNF superfamily pathway genes in the SARS CoV-2 vCTLs as compared to pre-stimulated PBMNCs. Conclusion: Our study demonstrates that highly functional SARS-CoV-2 vCTLs can be rapidly generated by direct cytokine enrichment from convalescent donor peripheral blood mononuclear cells. These data serve as pre-clinical validation for an ongoing clinical trial utilizing related HLA-matched and haplo-identical SARS CoV-2 vCTLs for the treatment of patients with mild and moderate SARS-CoV-2 disease (IND #27260, NCT# 04896606). Figure 1 Figure 1. Disclosures Lee: Kiadis Pharma: Divested equity in a private or publicly-traded company in the past 24 months, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Courier Therapeutics: Current holder of individual stocks in a privately-held company. Johnson: Miltenyi Biotec: Research Funding. Cairo: Jazz Pharmaceutical: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Speakers Bureau; Sanofi: Speakers Bureau; Servier: Speakers Bureau; Sobi: Speakers Bureau; Omeros: Membership on an entity's Board of Directors or advisory committees; Nektar: Membership on an entity's Board of Directors or advisory committees.

scholarly journals Impact of Modified Thalidomide Dosing in Bortezomib/Thalidomide/Dexamethasone for Patients with Newly Diagnosed Multiple Myeloma Who Are Transplant-Eligible: A Matching-Adjusted Indirect Comparison

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4739-4739
Author(s):  
Pieter Sonneveld ◽  
Maria-Victoria Mateos ◽  
Adrián Alegre ◽  
Thierry Facon ◽  
Cyrille Hulin ◽  
...  
Keyword(s):  
Peripheral Neuropathy ◽  
Board Of Directors ◽  
Research Funding ◽  
Indirect Comparison ◽  
Employment Equity ◽  
Advisory Committees ◽  
Post Transplant ◽  
Post Induction ◽  
Adjusted Indirect Comparison ◽  
Equity Ownership

Introduction: For patients with newly diagnosed multiple myeloma (NDMM) who are transplant-eligible, bortezomib/thalidomide/dexamethasone (VTd) is a standard of care (SoC) for induction and consolidation therapy. Clinical practice has evolved to use a modified VTd dose (VTd-mod; 100 mg thalidomide daily), which is reflected in recent treatment guidelines. As VTd-mod has become a real-world SoC, a matching-adjusted indirect comparison (MAIC) of the VTd-mod dose from recent clinical trials versus the dose included in the label (VTd-label; ramp up to 200 mg thalidomide daily) was performed to understand the effect on efficacy of modified VTd dosing for patients with NDMM who are transplant-eligible. Methods: For each outcome (overall survival [OS], progression-free survival [PFS], overall response rates [ORR] post-induction and post-transplant, and rate of peripheral neuropathy), a naïve comparison and a MAIC were performed. Data for VTd-label were obtained from the phase 3 PETHEMA/GEM study (Rosiñol L, et al. Blood. 2012;120[8]:1589-1596). Data for VTd-mod were pooled from the phase 3 CASSIOPEIA study (Moreau P, et al. Lancet. 2019;394[10192]:29-38) and the phase 2 NCT00531453 study (Ludwig H, et al. J Clin Oncol. 2013;31[2]:247-255). Patient-level data for PETHEMA/GEM and CASSIOPEIA were used to generate outcomes of interest and were validated against their respective clinical study reports; aggregate data for NCT00531453 were extracted from the primary publication. Matched baseline characteristics were age, sex, ECOG performance status, myeloma type, International Staging System (ISS) stage, baseline creatinine clearance, hemoglobin level, and platelet count. Results: Patients received VTd-mod (n = 591) or VTd-label (n = 130). After matching, baseline characteristics were similar across groups. For OS, the naïve comparison and the MAIC showed that VTd-mod was non-inferior to VTd-label (MAIC HR, 0.640 [95% CI: 0.363-1.129], P = 0.121; Figure 1A). VTd-mod significantly improved PFS versus VTd-label in the naïve comparison and MAIC (MAIC HR, 0.672 [95% CI: 0.467-0.966], P = 0.031; Figure 1B). Post-induction ORR was non-inferior for VTd-mod versus VTd-label (MAIC odds ratio, 1.781 [95% CI: 1.004-3.16], P = 0.065). Post-transplant, VTd-mod demonstrated superior ORR in both the naïve comparison and MAIC (MAIC odds ratio, 2.661 [95% CI: 1.579-4.484], P = 0.001). For rates of grade 3 or 4 peripheral neuropathy, the naïve comparison and MAIC both demonstrated that VTd-mod was non-inferior to VTd-label (MAIC rate difference, 2.4 [⁻1.7-6.49], P = 0.409). Conclusions: As naïve, indirect comparisons are prone to bias due to patient heterogeneity between studies, a MAIC can provide useful insights for clinicians and reimbursement decision-makers regarding the relative efficacy and safety of different treatments. In this MAIC, non-inferiority of VTd-mod versus VTd-label was demonstrated for OS, post-induction ORR, and peripheral neuropathy. This analysis also showed that VTd-mod significantly improved PFS and ORR post-transplant compared with VTd-label for patients with NDMM who are transplant-eligible. A limitation of this analysis is that unreported or unobserved confounding factors could not be adjusted for. Disclosures Sonneveld: Takeda: Honoraria, Research Funding; SkylineDx: Research Funding; Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; BMS: Honoraria; Amgen: Honoraria, Research Funding; Karyopharm: Honoraria, Research Funding. Mateos:Janssen, Celgene, Takeda, Amgen, Adaptive: Honoraria; AbbVie Inc, Amgen Inc, Celgene Corporation, Genentech, GlaxoSmithKline, Janssen Biotech Inc, Mundipharma EDO, PharmaMar, Roche Laboratories Inc, Takeda Oncology: Other: Advisory Committee; Janssen, Celgene, Takeda, Amgen, GSK, Abbvie, EDO, Pharmar: Membership on an entity's Board of Directors or advisory committees; Amgen Inc, Celgene Corporation, Janssen Biotech Inc, Takeda Oncology.: Speakers Bureau; Amgen Inc, Janssen Biotech Inc: Other: Data and Monitoring Committee. Alegre:Celgene, Amgen, Janssen, Takeda: Membership on an entity's Board of Directors or advisory committees. Facon:Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Hulin:celgene: Consultancy, Honoraria; Janssen, AbbVie, Celgene, Amgen: Honoraria. Hashim:Ingress-Health: Employment. Vincken:Janssen: Employment, Equity Ownership. Kampfenkel:Janssen: Employment, Equity Ownership. Cote:Janssen: Employment, Equity Ownership. Moreau:Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria.

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